For the first time, we have characterized mature human B cells that have an anergic phenotype, providing a critical link to twenty years of research in mice. These IgM-Low naive B cells are predominantly autoreactive and they have a reduced capacity to flux calcium, phosphorylate tyrosines or survive after stimulation. Intense stimulation causes these cells to be activated, consistent with the long-standing view that anergic B cells may be a source of pathological autoantibodies in diseases such as systemic lupus erythematosus. The long term goal of the experiments proposed herein is to translate our new basic understanding of a central mechanism of immune tolerance in humans, anergy, into a new thinking that will lead to tangible treatments of lupus. We suspect there are defects in anergic B cells that may be typical in various lupus patients, each of which could substantially alter our understanding and treatment strategies of this disease. We hypothesize that anergy is not induced or maintained for autoreactive B cells in SLE patients, allowing these cells to become fully functional. Anergic B cells may be a pool of autoreactive B cells that produce pathological autoimmune responses. To test these hypotheses in Specific aim 1, we will use flow cytometry and molecular variable gene analysis to compare the frequency and phenotype of anergic B cells in a cohort of lupus patients with age and sex matched unaffected controls. In specific aim 2 we will determine if anergic B cells in lupus patients have altered function and the molecules involved, leading to full immune reactivity despite being autoreactive. In specific Aim 3 we will compare the specificities and affinities of a panel of recombinant human monoclonal antibodies from anergic B cells of lupus patients to antibodies from healthy controls. With this analysis we will identify natural autoantigens that may escape tolerance and cause pathology in SLE patients.